The levodopa, chemically known also as L-(-)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid or as 3,4-dihydroxyphenyl-L-alanine or as 3-hydroxy-L-thyrosine, is an aminoacid of natural origin known since long time for its pharmacological activity in the treatment of the Parkinson's disease.
Its synthesis has been described in many publications like Helv. Chem. Acta, 4, 657, (1921), starting from the 3-nitro-L-thyrosine, Chem. Pharm. Bull., 10, 693, (1962) starting from 3-(3,4-methylenedioxyphenyl)-L-alanine and Ber. 105, 1168, (1972) starting from L-thyrosine.
The synthesis of levodopa by different ways was described in many patent documents. Asymmetric chemical synthesis, enzymatic and fermentative synthesis and methods for the optical resolution of precursors of the levodopa itself were reported. In the U.S. Pat. No. 4,005,127 an asymmetric chemical synthesis is described by catalytic asymmetric hydrogenation of a racemic mixture of alfa-acetamido-4-hydroxy-3-alkoxy-cinnamic acids in presence of a stereospecific catalyst made by a coordination complex between a noble metal and an optically active phosphine or arsine.
Processes by enzymatic and fermentative way are described in the German Patent Publication No. DT-OS 2102793, by fermentation of the L-thyrosine, in the U.S. Pat. No. 3,838,008, by stereoselective hydrolysis of N-acylderivatives with Escherichia coli acylase and in European Patent Publication EP0189938, by reaction between protected 3,4-dihydroxyphenyl pyruvic acids and glutamic or aspartic acid in presence of aminotransferase produced by genetically modified Escherichia coli.
Processes for the optical resolution of precursors of the levodopa, followed by hydrolysis, are described in the Belgian Patent No. BE 743496, resolution of the d,l-N-acetyl-3-(3,4-dimethoxyphenyl)alanine with d-.alpha.-methylbenzylamine, in the German Publication No. DT-OS 1963991, resolution of the d,l-N-benzoyl-3,4-dihydroxyphenylalanine with cinchonidine, in the German publication No. DT-OS 2039253, resolution of the d,l-N-benzoyl-3,4-dimethoxyphenylalanine with D-(-)-threo-1-m-nitrophenyl-2-amino-1,3-propandiol and in the U.S. Pat. No. 4,716,246, selective crystallization of the d,1-N-acetyl-3-(4-acetoxy-3-methoxyphenyl)alanine.
The process for the synthesis of the levodopa described in the present invention is completely new and consists in the optical resolution of the d,l-2-amino-3-(3,4-dimethoxyphenyl)propionitrile with d-camphorsulfonic acid and in the subsequent hydrolysis and demethylation of the d-2-amino-3-(3,4-dimethoxyphenyl)propionitrile.
The d,l-2-amino-3-(3,4-dimethoxyphenyl)propionitrile is known from the Israeli Pat. No. IL 59048, but the method for its synthesis described in the present invention is totally different. Moreover, both its separation into the corresponding enantiomers and the hydrolysis followed by the demethylation of the d enantiomer, to obtain the desired end product, are unknown.